Nabil Adra

High-Dose Chemotherapy and Autologous Peripheral-Blood Stem-Cell Transplantation for Relapsed Metastatic Germ Cell Tumors: The Indiana University Experience

Purpose Patients with relapsed metastatic germ cell tumor (GCT) can be cured with second-line and even third-line regimens. We report survival outcomes of patients treated with high-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplantation (PBSCT) at Indiana University between 2004 and 2014. Patients and Methods We conducted a retrospective analysis of 364 consecutive patients with GCT who progressed after cisplatin-based combination chemotherapy and were subsequently treated with HDCT and PBSCT. Three hundred forty-one patients received two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. Twenty-three patients received only a single course of HDCT because of progressive disease or toxicity. Cox proportional hazards models were used to test predictors of disease progression. Results The median age was 32 years (range, 17 to 70 years). With a median follow-up of 3.3 years, the 2-year progression-free survival (PFS) was 60% (95% CI, 55% to 65%) and the 2-year overall survival was 66% (95% CI, 60% to 70%). Three hundred three patients received HDCT as second-line therapy with a 2-year PFS of 63% (95% CI, 57% to 68%), and 61 patients received HDCT as third-line or later therapy with a 2-year PFS of 49% (95% CI, 36% to 61%). In a multivariable analysis, factors associated with disease progression included use of HDCT as third-line or later therapy, platinum-refractory disease, mediastinal primary tumor site, nonseminoma histology, intermediate- or poor-risk disease at the time of GCT diagnosis, and human chorionic gonadotropin ≥ 1,000 mIU/mL at initiation of HDCT. There were nine treatment-related deaths. Secondary leukemia developed in five patients. Conclusion This large single-institution study demonstrates that patients with relapsed metastatic GCT are curable by HDCT plus PBSCT even when used in third-line or later therapy.

Prognostic factors in patients with poor-risk germ-cell tumors: a retrospective analysis of the Indiana University experience from 1990 to 2014

BACKGROUND Based on the risk stratification from the International Germ Cell Cancer Collaborative Group (IGCCCG), only 14% of patients with metastatic germ-cell tumors (GCT) had poor-risk disease with a 5-year progression-free survival (PFS) rate of 41% and a 5-year overall survival (OS) rate of only 48%. This analysis attempts to identify prognostic factors for patients with poor-risk disease. PATIENTS AND METHODS We conducted a retrospective analysis of all patients with GCT diagnosed and treated at Indiana University from 1990 to 2014. Clinical and pathological characteristics were available for all patients and all of them were treated with cisplatin-etoposide-based chemotherapy. Cox proportional hazards models were used to target significant predictors of disease progression and mortality. A significance level of 5% was used in the analysis. RESULTS We identified 273 consecutive patients with poor-risk GCT (PRGCT). Median follow-up time was 8 years (range 0.03-24.5). The 5-year PFS and OS rates were 58% [95% confidence interval (CI) 51% to 63%] and 73% (95% CI 67% to 78%), respectively. In multivariate survival analyses, multiple risk factors were associated with disease progression, including liver metastasis, brain metastasis, primary mediastinal nonseminomatous GCT (PMNSGCT), and elevation in logarithmic β-hCG. Significant predictors of mortality were PMNSGCT [hazard ratio (HR) 4.63, 95% CI 2.25-9.56; P < 0.001], brain metastasis (HR 3.30, 95% CI 1.74-6.23; P < 0.001), and increasing age (HR 1.03, 95% CI 1.01-1.06; P = 0.02). CONCLUSIONS Patients with PMNSGCT, brain metastasis, or with increasing age are at higher risk of death than their counterparts. This contemporary cohort (1990-2014) of 273 patients with PRGCT had improved PFS and OS outcomes than those from the historical IGCCCG group of patients (1975-1990).

Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206

Background Despite remarkable results with salvage standard-dose or high-dose chemotherapy ∼15% of patients with relapsed germ-cell tumors (GCT) are incurable. Immune checkpoint inhibitors have produced significant remission in multiple tumor types. We report the first study of immunotherapy in patients with GCT. Patients and methods Single arm phase II trial investigating pembrolizumab 200 mg i.v. Q3weeks until disease progression in patients with relapsed GCT and no curable options. Patients age ≥18 with GCT who progressed after first-line cisplatin-based chemotherapy and after at least one salvage regimen (high-dose or standard-dose chemotherapy) were eligible. Centrally assessed programmed death-ligand 1 (PD-L1) on tumor and infiltrating immune cells was scored. Primary end point was overall response rate using immune-related response criteria. Simon two-stage design with type I error 20% and power 80% was utilized. Results Twelve male patients were enrolled. Median age was 38 years. All patients had nonseminoma. Primary site was testis (11) or mediastinum (1). Median AFP 615 (range 1-32, 760) and hCG 4 (range 0.6-37, 096). Six patients had late relapse (>2 years). Median number of previous chemotherapy regimens was 3. Six patients received prior high-dose chemotherapy. Two patients had positive PD-L1 staining (H-score 90 and 170). Median number of pembrolizumab doses was 2 (range 1-8). There were six grade 3 adverse events. No immune-related adverse events were reported. No partial or complete responses were observed. Two patients achieved radiographic stable disease for 28 and 19 weeks, respectively; both had continued rising AFP level despite radiographic stability and had negative PD-L1 staining. Conclusion This is the first reported trial evaluating immune checkpoint inhibitors in GCT. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT. Clinical trial information NCT02499952.

A Suggested Prognostic Reclassification of Intermediate and Poor-Risk Nonseminomatous Germ Cell Tumors

Micro‐Abstract In a large series of intermediate and poor risk nonseminomatous germ‐cell tumors we were able to identify new prognostic factors and to construct an improved risk classification system. Fewer cycles of cisplatin, etoposide, and bleomycin chemotherapy might be necessary in most cases to attain a cure. Background: The International Germ Cell Cancer Collaborative Group (IGCCCG) classification has been used since 1997 to allocate metastatic germ cell tumors (GCTs), but its applicability needs an update. We aimed to revisit the outcomes of intermediate and poor risk nonseminomatous GCTs (NSGCTs). Patients and Methods: Individual patient‐level data from the databases of 2 institutions were collected. Outcomes of consecutive patients who received first‐line chemotherapy from 1990 to 2014 were used. The Kaplan–Meier method was used to estimate relapse‐free (RFS) and overall survival (OS). Cox regression analyses were used to evaluate potential prognostic factors of RFS and OS univariably. Forward stepwise selection was used to construct a multivariable model. A risk factor (RF) model was then constructed and compared with IGCCCG classification using the concordance statistics (CS). Results: A total of 647 patients were identified. Four RFs for OS in the multivariable model were identified: primary mediastinal NSGCT (P < .001), brain metastases (P < .001), lung metastases (P = .016), and age at the time of diagnosis (P = .003). CS were improved on the basis of the number of RF (0, 1, 2, and 3 or 4) compared with IGCCCG (RFS: 0.63 vs. 0.58; OS: 0.65 vs. 0.59). For intermediate risk, there were no differences between 3 (n = 25) and 4 cycles of cisplatin, etoposide, and bleomycin (BEP; n = 159) or BEP × 3 + etoposide and cisplatin (EP) × 1 (n = 31) for RFS (P = .35) and OS (P = .061). Conclusion: An improved risk stratification was obtained for intermediate and poor risk GCTs. Our reclassification system might provide an aid for a reclassification attempt of all GCT patients. Our prognostic model might be offered to clinicians to improve their ability to assess patient prognosis, enhance stratification, and inform patients.

Chemotherapy-Related Chronic Myelogenous Leukemia: A Case Series of Patients With Germ Cell Tumor.

decrease the likelihood of discovering unknown toxic effects in larger populations and costly phase 2 and 3 studies. That (2) prospectively delineating therapeutic intent with prespecified clinical end points should be adopted because it may facilitate early identification of efficacy and improve insurance coverage of and patient access to early-phase trials.2 The ability to directly attribute late toxic effects to specific drug radiation combinations is complicated by early patient mortality and confounding treatments. However, because investigators are obligated to their patients and peers to evaluate toxic effects from investigational treatments, we propose that (3) assessment and reporting of late toxic effects be included in phase 1 trials. Limitations of this study include the time period evaluated, that it is a single database query, and that it only includes published trials and toxic effects. ClinicalTrials.gov was not included because trial registration is not mandated as a condition of publication for phase 1 trials.6 However, these data identify 3 important measures, which if addressed, will improve the quality, availability, and interpretability of phase 1 trials.

Risk of Bleomycin-Related Pulmonary Toxicities and Operative Morbidity After Postchemotherapy Retroperitoneal Lymph Node Dissection in Patients With Good-Risk Germ Cell Tumors

PURPOSE Three cycles of bleomycin, etoposide, and cisplatin (BEP × 3) or four cycles of etoposide and cisplatin (EP × 4) are first-line chemotherapy regimens for men with International Germ Cell Cancer Collaborative Group (IGCCCG) good-risk germ cell tumors (GCTs). We determined whether inclusion of bleomycin affected pulmonary and operative morbidity after postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). PATIENTS AND METHODS We queried our database to identify IGCCCG good-risk patients who received BEP × 3 or EP × 4 induction chemotherapy before PC-RPLND from 2006 to 2016. Patients who received combination regimens were excluded. The primary outcomes of interest were pulmonary morbidity (prolonged intubation, reintubation, supplemental oxygen use, intensive care unit stay) and operative morbidity (operative time, length of stay, concomitant procedures, estimated blood loss). RESULTS We analyzed 234 patients (191 BEP × 3 v 43 EP × 4). All patients were extubated immediately after the operation. None were reintubated or discharged on oxygen. Two patients in each cohort required an intensive care unit stay for nonpulmonary reasons. Patients treated with BEP required shorter use of supplemental oxygen (0.99 v 1.63 days; P = .005). No significant differences were found in preoperative mass size ( P = .42) or concomitant surgeries ( P = .58). Operative time was significantly shorter (131 v 170 minutes; P < .01), and estimated blood loss was considerably less (194 v 226 mL; P < .01) in patients treated with BEP. Length of stay was shorter in patients treated with BEP (3.3 v 3.9 days; P < .01). CONCLUSION In a modern surgical cohort, the inclusion of bleomycin does not seem to influence pulmonary morbidity, operative difficulty, or nonpulmonary postoperative complications after PC-RPLND in men with IGCCCG good-risk GST.

Metastatic small cell carcinoma of the prostate in an octogenarian with significant response to first-line chemotherapy

Patients with small cell carcinoma of the prostate generally present with metastatic disease and have an estimated life expectancy measured in months. In this brief report, we present a case of rapidly progressive metastatic small cell carcinoma of the prostate in an octogenarian with significant response to split-dosed cisplatin and etoposide. This case report shows that cautious treatment with platinum-based regimens should still be considered in elderly patients given the potential for improvement in performance status and quality of life with chemotherapy. Additionally, this case highlights that platinum-based regimens are still considered the therapeutic backbone of prostate cancers with a mixed small cell carcinoma and adenocarcinoma phenotype.

TMPRSS2-ERG Fusion in an Uncommon Presentation of Prostate Cancer

Patients with metastatic prostate cancer can present or relapse in peculiar fashion. Routine assessment of tumor pathology and immunohistochemistry can be diagnostic in many instances. However, some cases require more sophisticated testing to make the diagnosis. In this brief report, a patient with initially localized prostate cancer and undetectable prostate-specific antigen presented with a large mass in his sternum and mediastinal lymphadenopathy. The biopsy of the sternal mass was nonconclusive; hence, next generation sequencing was performed, showing transmembrane protease, serine 2 (TMPRSS2)-ETS gene fusion. TMPRSS2-ETS gene fusion appears to be specific and exclusive for prostate cancer and hence can be diagnostic, confirming the diagnosis of recurrent prostate cancer in this patient. When there is uncertainty regarding a diagnosis of prostate cancer, testing for TMPRSS2-ERG fusion by immunohistochemistry, fluorescence in situ hybridization, or DNA sequencing will result in the establishment of an accurate diagnosis.